Semaphorins are newcomers to the growing panoply of immunoregulatory proteins. Members of this family were originally identified as proteins that provide axonal guidance cues during neuronal development. However, accumulating evidence indicates that several semaphorins, called 'immune semaphorins', are crucial to various phases of the immune response, from initiation to terminal inflammatory processes. Extensive studies of immune semaphorins have shown not only differences but also parallels in semaphorin functions among physiologically distinct systems, providing unexpected but meaningful insights into the biological activities of this protein family. Here we review the present knowledge of the function of semaphorins and their receptors in the immune system, including the most recent advances in this field.